Alzheimer's disease is a degenerative brain disease which is characterised by progressive loss of memory and subsequently most other cognitive functions in an irreversible decline over a period of years. It represents a substantial health problem, particularly in an ageing population.
The amyloid precursor protein (“APP”) is a multifunctional transmembrane protein and is known to have important functions in normal brain tissue. The human form of APP is known to consist of 695 amino acid residues (SEQ ID No: 1) in a sequence which is also known (see Kang et al, Nature 325, 733-736 (1987), the contents of which are incorporated herein by reference). The chick form of APP is known to consist of 534 amino acid residues (SEQ ID No: 2) and to resemble the human form closely, being approximately 95% homologous therewith (see the paper by Kang et al just mentioned and Barnes et al, J Neurosci, 18 (15) 5869-5880 (1998), contents of which are also incorporated herein by reference). The amino acid sequences of the human and chick forms of APP are reproduced in FIG. 1 of the drawings of this specification.
Two effects which have been noted to take place in the brain of a person suffering from Alzheimer's disease are he build up outside the nerve cells of the brain of tangled masses of protein and the build up inside the brain cells of a different protein. The extracellular proteins are known to be aggregates of polypeptides having amino acid sequences corresponding to portions of the extracellular part of APP. The tangled masses of these proteins are known as amyloid plaques. The intracellular proteins are known as tau proteins. It is however not known whether either or both of the extracellular accumulation of amyloid plaques and the intracellular accumulation of tau proteins are the causes or the symptoms of Alzheimer's and related neurodegenerative diseases of the Alzheimer type.
The amino acid sequence of the β-amyloid polypeptide fragment (1-42) is identical in the human and chick forms of APP and consists of amino acid residues 597 to 638 in the human form and residues 436 to 477 in the chick form, (see the papers by Kang et al and Barnes et al referred to hereinbefore).
Definitions
The following expressions are used in this specification and have the following meanings:
APPmeans “amyloid precursor protein”;human APPmeans the human form of APP;chick APPmeans the chick form of APP;RERMSmeans the pentapeptide Arg-Glu-Arg-Met-Ser (SEQ ID No: 3);APP 328-332also means the pentapeptide Arg-Glu-Arg-Met-Ser (SEQ ID No: 3)which corresponds to amino acid.residues 328 to 332 of human APP;SMRERmeans the pentapeptide Ser-Met-Arg-Glu-Arg (SEQ ID No: 4);Aβ domainmeans the domain of APP whichforms β-amyloid plagues;β-amyloid 12-28means the sequence of amino acidresidues which constitute part ofthe Aβ domain of human APP, thesequence being Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys (SEQ ID No: 8)which corresponds to amino acidresidues 608 to 624 of human APPand amino acids 447 to 463 ofchick APP;RSAERmeans the pentapeptide Arg-Ser-Ala-Glu-Arg (SEQ ID No: 5); andAPP 319-335means the polypeptide Ala-Lys-Glu-Arg-Leu-Glu-Ala-Lys-His-Arg-Glu-Arg-Met-Ser-Gln-Val-Met(AKERLEAKHRERMSQVM) (SEQ ID No:6).RERmeans the tripeptide Arg-Glu-Arg(SEQ ID No: 9).RERMmeans the tetrapeptide Arg-Glu-Arg-Met (SEQ ID No: 10).MRERmeans the tetrapeptide Met-Arg-Glu-Arg (SEQ ID No: 11).Amino acidas used herein is meant to includeboth natural and synthetic aminoacids, and both D and L aminoacids.Standard amino acidmeans any of the twenty standardL-amino acids commonly found innaturally occurring peptides.Nonstandard amino acidmeans any amino acid, other thanthe standard amino acids,regardless of whether it isprepared synthetically or derivedfrom a natural source. As usedherein, “synthetic amino acid”also encompasses chemicallymodified amino acids, includingbut not limited to salts, aminoacid derivatives (such as amides),and substitutions. Amino acidscontained within the peptides ofthe present invention, andparticularly at the carboxy- oramino-terminus, can be modified bymethylation, amidation,acetylation or substitution withother chemical groups which canchange the peptide's circulatinghalf life without adverselyaffecting their activity.Additionally, a disulfide linkagemay be present or absent in thepeptides of the invention.Derivativeincludes any purposefullygenerated peptide which in itsentirety, or in part, has asubstantially similar amino acidsequence to the present compounds.Derivatives of the presentcompounds may be characterized bysingle or multiple amino acidsubstitutions, deletions,additions, or replacements. Thesederivatives may include (a)derivatives in which one or moreamino acid residues of the presentcompounds are substituted withconservative or non-conservativeamino acids; (b) derivatives inwhich one or more amino acids areadded to the present compounds;(c) derivatives in which one ormore of the amino acids of thepresent compounds include asubstituent group; (d) derivativesin which the present compounds ora portion thereof is fused toanother peptide (e.g., serumalbumin or protein transductiondomain); (e) derivatives in whichone or more nonstandard amino acidresidues (i.e., those other thanthe 20 standard L-amino acidsfound in naturally occurringproteins) are incorporated orsubstituted into the presentcompounds sequence; and (f)derivatives in which one or morenonamino acid linking groups areincorporated into or replace aportion of the present compounds.
Throughout this specification and its claims amino acid sequences are written using the standard one-letter or three-letter abbreviations. All sequences are written from left to right in the direction from the N-terminal to the C-terminal.
The following term is defined as follows:
reverse order sequenceas used herein, the reverse order sequence ofa given sequence is a sequence in which theorder of amino acid residues is reversedcompared with the given sequence whenreading in the direction from the N-terminalto the C-terminal and vice versa. Thus, forexample, SMRER is the reverse order sequenceof RERMS, each being read as stated above fromleft to right in the N-terminal to C-terminaldirection. Further, MVQSMRERHKAELREKA(SEQ ID No: 7) is the reverse order sequence ofAPP 319-335 defined above.